The Role of PPARγ in Human Placental Development and Preeclampsia

PPARγ 在人类胎盘发育和先兆子痫中的作用

• 批准号: 9253091
• 负责人: Sascha Drewlo
• 金额: $ 14.91万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253091
• 关键词: Address; Affect; Angiogenic Proteins; Apoptosis; Binding; Biological Assay; Blood; Blood Vessels; Cessation of life; Chorionic villi; Culture Media; Disease; Endothelial Cells; Endothelium; Foundations; GCM1 gene; Gene Silencing; Genes; Genetic Transcription; Goals; Human; Human Development; Hypertension; Hypoxia; In Vitro; Intervention; KDR gene; Link; Maternal Health; Maternal Mortality; Measures; Mediating; Modeling; Molecular Genetics; Mothers; Mus; Neuroglia; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; PPAR gamma; Pathologic; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Physiology; Pioglitazone; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Proteins; Premature Birth; Protein Secretion; Proteins; Proteinuria; Rattus; Regulation; Research; Rodent; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Thiazolidinediones; Tissues; Transcriptional Regulation; Vascular Diseases; Villous; angiogenesis; base; clinically relevant; economic cost; endothelial dysfunction; fetal; genetic approach; heme oxygenase-1; improved; inhibitor/antagonist; maternal morbidity; novel; pathophysiology of preeclampsia; programs; promoter; protein expression; public health relevance; rosiglitazone; transcription factor; trophoblast

DESCRIPTION (provided by applicant): Severe preeclampsia (sPE) is a placenta-based hypertensive disorder affecting 2 to 7% of all pregnancies. It is the leading cause of fetal and maternal morbidity and mortality worldwide. The Preeclampsia Foundation (2007) estimates the annual economic cost of sPE in the USA to be $7 billion. Presently, the only available cure for this disease is placental and fetal delivery. In severe cases, this disease leads to preterm birth which, in itself, has numerous serious long- term complications. The ultimate goal of this project is to improve pregnancy outcome by ameliorating placental and maternal endovascular function in severe preeclampsia. sPE placentas are characterized by abnormal trophoblast differentiation, which, together with reduced uteroplacental perfusion, results in a hypoxic state leading to abnormal placental secretion of proteins, which in turn contribute to maternal vascular dysfunction, proteinuria and hypertension. The transcription factor and nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARγ), has recently been found to regulate the transcription factor GCM1, which regulates trophoblast differentiation and is reduced in sPE. PPARγ can be manipulated by drugs of the thiazolidinedione class, which are normally used for the treatment of type II diabetes. Using Rosiglitazone in a rat model of sPE, we have shown great improvements in pregnancy outcome and maternal vascular function. We hypothesize that human trophoblast differentiation is regulated by the PPARγ-GCM1 axis and that it can be induced pharmacologically to improve placental and, in turn, maternal endothelial function. Furthermore, we challenge the current tenet that pathological protein secretion in preeclampsia is primarily caused by hypoxia, and suggest instead that it is driven by abnormal differentiation. This hypothesis will be critically tested by completing the following three specifc aims; 1. We will assess whether PPARγ regulates human trophoblast differentiation by direct regulation of the transcription factor GCM1 as part of a cascade that in turn regulates many other proteins. 2. We will test whether modulation of PPARγ activity will improve placental function in a hypoxic placental explant model of sPE. 3. We will determine whether placental protein secretion can be altered through modulation of PPARγ activity to drive trophoblast differentiation, and whether this, in turn, will improve maternal endothelial function. The efficac of this strategy will be assessed by determining in an angiogenesis assay whether media from pathological tissues treated with PPARγ activating drugs will improve endothelial function. Successful completion of this study will explain new pathways in human placental development and the pathophysiology of preeclampsia.

描述（由申请人提供）：重度先兆子痫（sPE）是一种以胎盘为基础的高血压疾病，占所有妊娠的2%至7%。它是全世界胎儿和孕产妇发病率和死亡率的主要原因。先兆子痫基金会（2007）估计，sPE在美国每年的经济成本为70亿美元。目前，唯一有效的治疗方法是胎盘和胎儿分娩。在严重的情况下，这种疾病会导致早产，这本身就有许多严重的长期并发症。该项目的最终目标是通过改善重度子痫前期胎盘和母体血管内功能来改善妊娠结局。sPE胎盘的特点是滋养细胞分化异常，再加上子宫胎盘灌注减少，导致缺氧状态，导致胎盘蛋白分泌异常，进而导致母体血管功能障碍、蛋白尿和高血压。转录因子和核受体，过氧化物酶体增殖激活受体γ (PPARγ)，最近被发现可以调节转录因子GCM1， GCM1调节滋养细胞分化，并在sPE中减少。PPARγ可以被噻唑烷二酮类药物控制，这类药物通常用于治疗II型糖尿病。在sPE大鼠模型中使用罗格列酮，我们已经显示出妊娠结局和母体血管功能的巨大改善。我们假设人类滋养细胞分化是由PPARγ-GCM1轴调控的，并且可以通过药物诱导来改善胎盘，进而改善母体内皮功能。此外，我们对目前认为子痫前期病理性蛋白分泌主要是由缺氧引起的观点提出了质疑，并认为它是由异常分化驱动的。这一假设将通过完成以下三个具体目标进行严格检验；1. 我们将评估PPARγ是否通过直接调节转录因子GCM1来调节人类滋养细胞分化，GCM1作为级联反应的一部分，反过来调节许多其他蛋白质。2. 我们将在sPE缺氧胎盘移植模型中测试PPARγ活性的调节是否会改善胎盘功能。3. 我们将确定胎盘蛋白分泌是否可以通过调节PPARγ活性来驱动滋养细胞分化，以及这是否反过来会改善母体内皮功能。这一策略的有效性将通过血管生成实验来评估，以确定病理组织的介质用PPARγ激活药物治疗是否会改善内皮功能。这项研究的成功完成将解释人类胎盘发育的新途径和子痫前期的病理生理。